1. Field of the Invention
This invention relates to novel 1H-indole-1-glyoxylamides, 1H-indole-1-acetamides, and 1H-indole-1-hydrazides useful for inhibiting sPLA.sub.2 mediated release of fatty acids for conditions such as septic shock.
2. Background Information
The structure and physical properties of human non-pancreatic secretory phospholipase A.sub.2 (hereinafter called, "sPLA.sub.2 ") has been thoroughly described in two articles, namely, "Cloning and Recombinant Expression of Phospholipase A.sub.2 Present in Rheumatoid Arthritic Synovial Fluid" by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, issue of Apr. 5, pp. 5335-5338, 1989; and "Structure and Properties of a Human Non-pancreatic Phospholipase A.sub.2 " by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of Apr. 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA.sub.2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA.sub.2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA.sub.2 ; such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and etc.
The article, "No. 565. -Inhibiteurs d'enzymes. XII. Preparation de (propargyamino-2 ethyl)-3 indoles" by A. Alemanhy, E. Fernandez Alvarez, O. Nieto Lopey and M. E. Rubio Herraez; Bulletin DO La Societe Chimiqque De France, 1974, No. 12, pgs. 2883-2888 describes various indolyl-3 glyoxamides which are hydrogen substituted on the 6 membered ring of the indole nucleus.
The article "Indol-Umlagerung von 1-Diphenylamino-2,3-dihydro-2,3-pyrroldionen" by Gert Kollenz and Christa Labes; Liebigs Ann. Chem., 1975, pgs. 1979-1983 describes phenyl substituted 3-glyoxylamides.
The abstract, "Nonnarcotic analgesic and antiinflammatory agents. 1-Carboxyalkyl-3-acylindoles" by Allais, Andre., et. al., Chemical Abstracts No. 131402u, Vol. 83, 1975 depicts indole formula with a --CH.sub.2 CO.sub.2 H group on the indole nitrogen.
The article, "Structure-activity relationships leading to WAY-121, 520, a tris aryl-type, indomethacin-based, phospholipase A.sub.2 (PLA.sub.2)/leukotriene biosynthesis inhibitor", by A Kreft, et. al., Agents and Actions, Social Conference Issue Vol. 39 (1993),pp. C33-C35, ISSN 0065-4299, published by Birkhauser Verlag, Basel Switzerland; (Proceedings of the Sixth International Conference of the Inflammation Research Association, Sep. 20-24, 1992, at White Haven, PA/USA, Guest Editors, D. W. Morgan and A. K. Welton) describes the inhibition of phospholipase A2 by indomethacin analogs. Indole compounds having benzyl and acidic substituents are described.
The article, "Some Analogs of 1-p-chlorobenzyl-5-methylindole-3-acetic acid" by E. Walton, et. al., J. Med. Chem., Vol. 11, 1968, pp. 1252-1255, describes the preparation of isomeric methyl 3-1-(1-p-chlorobenzyl-5-methoxy-3-methyl indole-2) propionate.
European Patent 490263 discloses oxoacetamide derivatives of indoles having serotonin receptor activity.
U.S. Pat. No. 1,825,734 describes the preparation of 3-(2-amino-1-hydroxyethyl) indoles using 3-indole glyoxylamide intermediates such as 1-phenethyl-2-ethyl-6-carboxy-N-propyl-3-indoleglyoxylamide (see, Example 30).
U.S. Pat. No. 2,890,233 describes several amide derivatives of 3-indoleacetic acids.
U.S. Pat. No. 3,271,416 describes indolyl aliphatic acids as sun screening agents and intermediates. These acids may be --NH.sub.2 substituted.
U.S. Pat. No. 3,351,630 describes alpha-substituted 3-indolyl acetic acid compounds and their preparation inclusive of glyoxylamide intermediates.
U.S. Pat. No. 3,449,363 describes trifluoromethylindoles having glyoxylamide groups at the 3 position of the indole nucleus. These compounds are stated to be analgesics in antagonizing phenyl-p-quinone "writhing syndrome."
World Patent application WO 9206088 describes indole compounds useful for treatment of circulatory diseases, chromosis and renal diseases.
Chemical Abstracts Vol. 83, 1975 131402u, "Nonarcotic analgetic and antiinflammatory agents. 1-Carboxyalkyl-3-acylindoles", describes various analgesic and antiinflammatory indolencetic acids.
U.S. Pat. No. 4,397,850 prepares isoxazolyl indolamines using glyoxylamide indoles as intermediates.
U.S. Pat. No. 5,132,319 describes certain 1-(hydroxylaminoalkyl) indoles derivatives as inhibitors of leukotriene biosynthesis.
It is desirable to develop new compounds and treatments for sPLA.sub.2 induced diseases.